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ERC

InMec Report Summary

Project ID: 341131
Funded under: FP7-IDEAS-ERC
Country: Italy

Mid-Term Report Summary - INMEC (Inside mechanisms sustaining cancer stem cells)

The “cancer stem cell” hypothesis postulates that individual tumours contain a sub-class of often-rare cancer cells, named Tumour Initiating Cells (TICs) or Cancer Stem Cells (CSCs), which are responsible for tumour growth and can support tumour heterogeneity. The “CSC Hypothesis” has important implications for cancer treatment as eradication of CSCs might be an essential requirement to achieve cancer cure, and persistent CSCs might explain disease recurrence after treatment. Notably, available anti-cancer drugs were selected in early clinical trials for their ability to reduce tumour size, an attribute that does not necessarily entail eradication of the rare population of CSCs. There are, however, many challenges within the CSC hypothesis, and whether CSCs are necessary and sufficient to sustain cancer growth is not definitively ascertained.
The final goal of our project is to elucidate the molecular mechanisms underlying the altered self-renewal properties of CSCs, and to determine how they contribute to the sustainability of tumour growth and to the generation of tumour heterogeneity. We are addressing these issues in two model systems, Acute Myeloid leukaemia (AML) and breast cancers, along four main lines of research.
In the first, we have found that the Myc oncogene induces progenitor reprogramming as a consequence of the loss of the tumour suppressor p53, and that its expression is sufficient to maintain the growth properties of CSCs. A manuscript has been submitted.
The second line of research studies other deregulated pathways which might contribute to increase CSC numbers in the tumour tissues. Two original papers have been already published. The first manuscript shows that an isoform of the protein p63 sustains the self-renewal potential of mammary CSCs by potentiating the activation of the Sonic Hedgehog pathway through direct regulation of its components. The second paper describes the identification by RNAi screens of a gene, CHD4, which appears essential in breast cancer growth. Other studies in AML are ongoing.
We are also investigating the mechanisms of self-renewal extension in CSCs. We have identified genes involved in the regulation of stem cell (SCs) quiescence (SC Quiescence signature); many of these genes are also critical for the maintenance of leukaemia growth. In addition, we have examined a potential oncogenic role for the E3 ubiquitin ligase WWP1 in the pathogenesis of AML, since both the proteins p53 and p63 (see above) are targets of WWP1-mediated ubiquitination, a mechanism which, ultimately, leads to their inactivation (manuscript submitted).
Finally, we are studying the effect of the DNA damage induced by the expression of oncogenes and the mechanisms of DNA-repair in tumour development and progression. Our data suggest that the analysis of the genomic distribution of DNA double strand breaks in healthy individuals can be used to predict the probability of developing cancer-associated chromosome abnormalities (manuscript submitted).

Reported by

ISTITUTO EUROPEO DI ONCOLOGIA SRL
Italy
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